Although the advent of highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV-1 infection, viral eradication is not achievable due to the persistence of latently- infected cells during treatment. Accumulating data suggest that non-AIDS cardiovascular, pulmonary, renal and hepatic diseases are amplified by HIV-1 infection, and even patients with viral suppression develop premature immune senescence. These realities have created a pronounced interest in developing strategies to eradicate HIV-1 in infected individuals. Recently, three cases have been reported that suggest a cure for HIV-1 may in fact be achievable. The Berlin Patient and two individuals from Boston, all of whom were HIV-positive and underwent allogeneic bone marrow transplantation, appear to be completely devoid of HIV-1 genetic material and exhibit waning anti-HIV-1 antibody levels. All three individuals share a common feature; they are heterozygous for the CCR5-delta 32 mutation (CCR5-?32). This 32 base pair deletion in the CCR5 gene affects the expression and stability of the CCR5 chemokine receptor which is utilized as an entry coreceptor by most HIV-1 strains. The three putative cases of HIV-1 eradication in CCR5-??32 heterozygotes warrant investigation into this mutation within the context of the HIV-1 reservoir and curative strategies. CCR5-??32 heterozygotes express significantly less CCR5 at the cell surface, impeding the entry of CCR5- tropic (R5) HIV-1. We hypothesize that CCR5-??32 heterozygotes harbor a smaller and less stable reservoir due to this deficit. Firstly, initial colonization of the HIV-1 reservoir is likely impeded in CCR5-??32 heterozygotes due to restriction of viral entry, resulting in a smaller reservoir before ART initiation. Secondly, the decay of the reservoir during ART may be accelerated in CCR5-??32 heterozygotes due to skewed cellular and tissue distribution of HIV-1, modulating the turnover rate, half-life and proliferative capacity of latently infected cells. This skewed distribution maybe driven in part by selection for alternative HIV-1 coreceptor usage in CCR5-??32 heterozygotes, including enrichment of CXCR4-using (X4) viruses which preferentially infect CXCR4-expressing cells such as naive CD4+ T cells. In this proposal, we will use a systems biology, translational approach to examine the size, cellular distribution, and viral genetic composition of the HIV-1 reservoir in the blood and lymphoid tissues of HIV-1-infected CCR5-??32 heterozygotes and case-matched CCR5 wildtype individuals. This study should yield valuable insights into the cellular and molecular determinants of HIV-1 persistence and eradication.